"May 2003" / Bibliography: leaves 72-87. / iii, 87 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Applied and Molecular Ecology, 2003

Graduation date: 1995

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (March 1, 2007) Vita. Includes bibliographical references.

Le système immunitaire nous protège contre les infections et les cancers. Cependant, des réponses immunitaires excessives ou incontrôlées peuvent causer des pathologies potentiellement mortelles comme le choc endotoxinique, des maladies auto-immunes, ou le rejet d’allogreffe. Une compréhension claire des mécanismes de régulation des réponses immunes permettrait d’envisager de nouvelles thérapeutiques plus ciblées. Dans ce travail réalisé chez la souris, la modulation de la réponse inflammatoire à une toxine bactérienne, le lipopolysaccharide (LPS), a été utilisée comme archétype de la régulation immunitaire. Ceci nous a permis de démontrer que la régulation de la prolifération homéostatique de lymphocytes T CD4+CD25- par des lymphocytes T régulateurs naturels tempère la réponse inflammatoire au LPS. Cet effet est notamment dépendant d’une diminution de la sécrétion d’IFN-γ par les lymphocytes activés par la prolifération induite par la lymphopénie. Nous avons aussi observé, que la désensibilisation du système immunitaire inné vis-à-vis du LPS, suite à des injections répétées d’endotoxine, induit le développement de cellules myéloïdes suppressives (myeloïd-derived suppressor cells MDSC) capables de réguler des réponses lymphocytaires T in vitro et in vivo. Nous avons pu mettre en évidence que l’effet suppresseur des MDSC est dépendant de leur expression de l’enzyme hème oxygénase-1 et de leur production d’IL-10. Le dialogue constant entre les cellules de l’immunité innée et de l’immunité acquise assure donc à la fois l’activation et la régulation du système immunitaire. Dans la majorité des cas, ceci permet aux réponses immunitaires d’être efficaces sans être excessives. La mise en évidence de ces processus identifie les lymphocytes T régulateurs et les cellules myéloïdes suppressives comme des éléments clefs de la régulation d’un processus inflammatoire. Les traitements immunosuppresseurs, les thérapies cellulaires et les greffes de moelle ont des effets variables et mal connu sur ces populations de cellules régulatrices. Tenir compte de ces interférences thérapeutiques avec les processus naturels de régulation de notre système immunitaire permettra certainement d’optimaliser l’utilisation de ce type de traitements. D’autre part, l’utilisation thérapeutique de ces deux types de cellules régulatrices pourrait être envisagé dans de nouvelles stratégies d’immuno-modulation plus « physiologique ».

The innate immune response is a primary transcriptional defence network activated by interferons (IFNs) α/ β in response to viral infection. A cell must have the capability to detect the virus, activate signalling cascades, and engage transcriptional anti-viral networks. IFNs trigger the Signal Transducer and Activator of Transcription (STAT) family, which in turn induce anti-viral gene expression. Recruitment of STATs to IFN stimulated gene (ISG) promoters and the ensuing gene induction requires Brahma Related Gene 1 (BRG1), the catalytic component of the SWI/ SNF chromatin remodelling (or BAF) complex. Cell lines with high BRG1 expression are hyper-responsive to IFN induced transcription, conversely BRG1 low cells exhibit impaired induction. However, BRG1 high cells that are resistant to Encephalomyocarditis virus infection did not require signalling through the IFN receptor complex for anti-viral immunity. This suggested 2F-BRG1 cells must rely on BRG1 dependent non-ISGs or an as yet uncharacterized subset of basally expressed BRG1-dependent ISGs that do not require IFN enhanced expression for anti-viral activity. Utilizing genome wide microarrays we identified five genes with potent anti-viral activity. These genes may restrict viral infection through alterations in integrin signalling, endosomal trafficking, and activation of host transcriptional responses. We also investigated the role of Special AT-Rich Binding Protein (SATB1) in regulation of IFN responsive genes. The loss of this chromatin binding protein is associated with transcriptional changes in the MHC locus that mimic IFNγ induced expression. Through microarray analysis we discovered a remarkable 47% of IFNα regulated genes were co-regulated by SATB1; 42% of IFNα induced genes were induced by SATB1 knock down, while 63% of IFNα repressed genes were SATB1 dependent. Functionally, knock down of SATB1 protected cells from EMCV induced cell death at low multiplicity of infection (MOI), and increased the cytoprotective effect of IFNα against EMCV at higher MOIs. Analysis of IFNα, SATB1 and BRG1 regulated genes revealed a subset of core genes regulated by all three factors that may be critical to robust anti-viral immunity. The potent immunosuppressive properties of SATB1 suggest this protein may be involved in complex immunopathologies. The immuno-modulatory properties of SATB1 and BRG1 established in this thesis provide substantive evidence for the development of pharmaceutical therapies targeting these proteins.

The recombinant Hepatitis B surface antigen vaccine inadequately protects those living with HIV from Hepatitis B virus infection. This study utilized saved serum samples from a retrospective cohort of persons with HIV and documented vaccine-induced HBsAb seroconversion to determine factors associated with persistence of protective levels of HBsAb (≥10mIU/ml). HBsAb levels fell below 10mIU/ml in 27% of the cohort after a median follow-up of 43 months. HIV viral load suppression (<50copies/ml) at the time of vaccination was the major factor associated with persistence of protective levels of HBsAb (OR 3.83, p <0.01). Among individuals who lost protective levels of HBsAb, booster doses of vaccine re-instated the development of protective levels of HBsAb. Delaying or repeating HBV vaccination until after suppression of HIV viral load is achieved should be considered HBV antibody levels should be followed over time and boosters given with loss of protective levels of HBsAb.

The recombinant Hepatitis B surface antigen vaccine inadequately protects those living with HIV from Hepatitis B virus infection. This study utilized saved serum samples from a retrospective cohort of persons with HIV and documented vaccine-induced HBsAb seroconversion to determine factors associated with persistence of protective levels of HBsAb (≥10mIU/ml). HBsAb levels fell below 10mIU/ml in 27% of the cohort after a median follow-up of 43 months. HIV viral load suppression (<50copies/ml) at the time of vaccination was the major factor associated with persistence of protective levels of HBsAb (OR 3.83, p <0.01). Among individuals who lost protective levels of HBsAb, booster doses of vaccine re-instated the development of protective levels of HBsAb. Delaying or repeating HBV vaccination until after suppression of HIV viral load is achieved should be considered HBV antibody levels should be followed over time and boosters given with loss of protective levels of HBsAb.

The innate immune response is a primary transcriptional defence network activated by interferons (IFNs) α/ β in response to viral infection. A cell must have the capability to detect the virus, activate signalling cascades, and engage transcriptional anti-viral networks. IFNs trigger the Signal Transducer and Activator of Transcription (STAT) family, which in turn induce anti-viral gene expression. Recruitment of STATs to IFN stimulated gene (ISG) promoters and the ensuing gene induction requires Brahma Related Gene 1 (BRG1), the catalytic component of the SWI/ SNF chromatin remodelling (or BAF) complex. Cell lines with high BRG1 expression are hyper-responsive to IFN induced transcription, conversely BRG1 low cells exhibit impaired induction. However, BRG1 high cells that are resistant to Encephalomyocarditis virus infection did not require signalling through the IFN receptor complex for anti-viral immunity. This suggested 2F-BRG1 cells must rely on BRG1 dependent non-ISGs or an as yet uncharacterized subset of basally expressed BRG1-dependent ISGs that do not require IFN enhanced expression for anti-viral activity. Utilizing genome wide microarrays we identified five genes with potent anti-viral activity. These genes may restrict viral infection through alterations in integrin signalling, endosomal trafficking, and activation of host transcriptional responses. We also investigated the role of Special AT-Rich Binding Protein (SATB1) in regulation of IFN responsive genes. The loss of this chromatin binding protein is associated with transcriptional changes in the MHC locus that mimic IFNγ induced expression. Through microarray analysis we discovered a remarkable 47% of IFNα regulated genes were co-regulated by SATB1; 42% of IFNα induced genes were induced by SATB1 knock down, while 63% of IFNα repressed genes were SATB1 dependent. Functionally, knock down of SATB1 protected cells from EMCV induced cell death at low multiplicity of infection (MOI), and increased the cytoprotective effect of IFNα against EMCV at higher MOIs. Analysis of IFNα, SATB1 and BRG1 regulated genes revealed a subset of core genes regulated by all three factors that may be critical to robust anti-viral immunity. The potent immunosuppressive properties of SATB1 suggest this protein may be involved in complex immunopathologies. The immuno-modulatory properties of SATB1 and BRG1 established in this thesis provide substantive evidence for the development of pharmaceutical therapies targeting these proteins.

No description available.

Abstract In order to determine whether antigens prepared from adult intestine of Angiostrongylus cantonensis have potential to induce a protective immunity in the rodent hosts, somatic antigens extracted from male and female adults as well as gut antigens isolated from female adults were used to immunize rats against A. cantonensis infection. A 14% reduction in L5 recorvery from brain as well as a 15% reduction in adult recovery from pulmonary artery were achieved in the immunized rats when compared with the control group after infection with 50 larvae. The length of worms recovered from immunized rats was shorter than that in other groups. The larvae recovered from fecal materials in immunized rats were also reduced. In cell proliferation test, the stimulation index of gut antigens increased with times of immunization and exhibited the highest values. However, serum IgG titers were not correlated with protective immune responses. A 84 kDa protein contained in all antigen preparations was recognized by immune serum against gut antigens. Strong positive reactions were detected by indirect immunofluorescent assay in the internal musculature of the body, gut and reproductive tract wall and gut lumen. The composition of gut antigens was similar to that of gut membrane proteins. Immune sera recognized several major gut proteins were also appeared on gut membrane proteins. Further studies are required to provide evidence that gut membrane proteins play in the protective immune response against A. cantonensis infections, including the 84 kDa protein.